This case is related to Merck case 18662.
Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase.
Squalene synthetase is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.
Previous efforts at inhibiting squalene synthetase have employed pyrophosphate or pyrophosphate analog containing compounds such as those described in P. Ortiz de Montellano et al, J. Med Chem. 20, 243 (1977) and E. J. Corey and R. Volante, J. Am. Chem. Soc., 98, 1291 (1976). S. Biller (U.S. Pat. No. 4,871,721) describes isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthetase.
Recently certain nonphosphorous containing inhibitors of squalene synthetase have been isolated as natural products. These natural product inhibitors are described in U.S. Pat. Nos. 5,053,425; 5,055,487 and 5,026,554. Certain squalestatins are discussed in Baxter, A. et al., J. Biol. Chem. 267, 11705 (1992); Dawson, M. J. et al., J. Antib. 45, 639 (1992); Sidebottom, P. J. et al., Antib. 45,648 (1992). See also EPO 494622 and PCT WO 92/12156.
U.S. Pat. No. 5,026,554 describes a squalene synthetase inhibitor of structure: ##STR1## which is hereafter referred to as Zaragozic acid C. This compound is produced by a solid fermentation employing a culture of Leptodontium elatius. The present invention discloses certain structurally related compounds to Zaragozic acid C which have now been isolated as minors from a fermentation broth using Leptodontium elatius.